Significance Changes in the alpha-2 adrenergic receptor density has been implicated in several disease states including hypertension, depression, diabetes and Alzheimer[unreadable]s disease as well as craving in drug abuse. No radiolabeled alpha-2 agent exists to study receptor density changes in vivo using nuclear medicine imaging techniques. Objectives The aim of this study was to evaluate the brain distribution of a fluorine-18 labeled alpha-2 adrenergic receptor ligands in the macaque using positron emission tomography. The primate model is well suited for preclinical PET studies based on the anatomic and functional similarities with the human brain. Results We studies two fluorine-18 radiopharmaceuticals, analogs of yohimbine. These compounds had previously demonstrated uptake in the rat brain which was displaceable by a non-radioactive alpha-2 adrenergic receptor ligand. When studied in the primate, we found that there was little or no radioactivity localized in the brain. These compounds were not able to cross the blood brain barrier. While this result was unexpected it is not totally surprising as the distribution of radiophamaceutical can be highly species dependent. We have recently found that preclinical trials in humans with nonradioactive analogs from this same class of compounds did not elicit the expected pharmacological response, corroborating our finding. For some, as of yet, unexplained reason these compounds are not reaching the neuroreceptor sites in the brain of higher order mammals. Future Directions We plan to explore other positron labeled alpha-2 adrenergic receptor ligands and determine their potential imaging characteristics in the primate model. KEYWORDS alpha-2 adrenergic receptor, Positron Emission Tomography (PET), imaging